2-aminotetralines, a process for their preparation, and pharmaceutical compositions, for the prevention and therapeutic treatment of inflammatory and/or autoimmune pathologies

ABSTRACT

2-Aminotetralines, a process for their preparation, and pharmaceutical compositions, for the prevention and therapeutic treatment of inflammatory pathologies (particularly septic shock) and/or autoimmune pathologies in which the aetiopathogenic role of inflammatory cytokines has been ascertained.

[0001] The invention described herein relates to derivatives of2-aminotetralines and their pharmacologically acceptable salts, aprocess for their preparation, pharmaceutical compositions suitable forprophylactic and therapeutic treatment of septic shock, and for thetreatment of inflammatory and/or autoimmune pathologies which will bebetter defined here below, in which the aetiopathogenetic role ofinflammatory cytokines is well established.

[0002] 6,7-Substituted-2-aminotetralines which are active in thetreatment of septic shock are well known.

[0003] EP-A-0 730 861, which is incorporated herein for referencepurposes, describes a class of such 6,7-substituted-2-aminotetralinesand particularly the compound (R,S)-2-amino-6-fluoro-7-methoxytetraline(hereinafter referred to as ST 626).

[0004] The inflammatory and/or autoimmune pathologies to be treated withthe compositions according to the invention described herein are, forexample, rheumatoid arthritis, pancreatitis, inflammatory bowel disease,systemic lupus erythematosus, glomerulonephritis and encephalomyelitis.

[0005] Hereinafter, reference will be made only to septic shock, itbeing understood that the other pathologies due to inflammatorycytokines can also be effectively treated according to the invention.

[0006] Septic shock is an extremely severe clinical syndrome which mayset in as a result of infections mainly caused either by gram-negativeor gram-positive bacteria, by protozoa or by viruses, and characterisedby leukocytosis, fever, tachycardia, hypotension and renal, respiratory,cardiac and hepatic insufficiency.

[0007] It should be stressed, however, that the severity of septic shockis independent of the type of micro-organism responsible for thesyndrome (Parrillo J. E., Pathogenetic mechanisms of septic shock. NewEngl. J. Med., 328:1471-1477, 1993) but is related to the extent of theindividual inflammatory response to the antigen responsible for thetoxic insult.

[0008] Despite the significant improvement in antibiotic therapy and inintervention protocols in intensive care units, over the past few years,shock remains one of the major causes of morbidity and mortality inhospitalised patients. It is estimated that in the USA it is responsiblefor approximately 100,000 deaths/year (Glauser M. P., Zanetti G.,Baumngartner J. D., Cohen J., Septic shock: pathogenesis. Lancet,338:732-736, 1991).

[0009] The most decisive and characteristic feature of septic shock isthe body's reaction to products deriving from lysis or from microbialmetabolism.

[0010] The first of these substances to be identified and the one mostused in experimental research is lipopolysaccharide (LPS); a constituentof the gram-negative bacteria wall, chemically consisting in apolysaccharide portion which varies according to the bacterial species,and a lipid portion (lipid A) which is constant, and present in theblood of septicaemic subjects in the form of micelles. If administeredto animals, LPS is capable of reproducing all the cardiocirculatory andneurological symptoms encountered in shock (Olson. N.C., Salzer W. L.,McCall C. E., Biochemical, physiological and clinical aspects ofendotoxaemia. Molec. Aspects Med., 10: 511-629, 1988). It is thereforeidentifiable as the prime mover in the chain of events which leads tothe triggering of the clinical symptoms via activation of the intrinsicand extrinsic pathways of the coagulative cascade and the secretion ofcytokines of mainly macrophage-monocyte origin, such as, for instanceTNF, IL-1 and INF-γ (Bone R. C., A critical evaluation of new agents forthe treatment of sepsis. J. Am. Med. Ass., 266: 1686-1691, 1991).

[0011] The increasing importance this syndrome has come to take on overthe past few years, its severity and the inadequate therapeutic meanscurrently available make the rapid discovery of therapeutic agentscapable of effectively combating the progression of the disease a highlydesirable goal.

[0012] It has now been found that a new class of 6,7-substituted2-aminotetralines exhibits potent activity in the prevention andtherapeutic treatment of the above-mentioned pathologies.2-Aminotetraline derivatives according to the invention can occur bothas free bases with general formula (I):

[0013] and as pharmacologically acceptable salts with general formula(II):

[0014] wherein:

[0015] R and R₁, are independently, halogen, particularly fluorine;hydroxy; C1-C4 alkoxy, particularly methoxy, optionally substituted inposition ω with groups OH, NH₂, NR₃R₄, where R₃ and R₄ are independentlyH, C1-C4 alkyl, unsubstituted or substituted in position o with groupsOH, NH₂;

[0016] C1-C4 alkanoyl, particularly acetyl; C1-C4 alkyl; carbamoyl;carbamoyloxy; amino; amino substituted NR₃R₄, where R₃ and R₄ have theabove-mentioned meanings;

[0017] R₂ is hydrogen; halogen, particularly fluorine; hydroxy; methoxy,with the proviso that the case is excluded in which the 2-aminotetralineis a raceme in which (a) R═R₁═CH₃₀; OH; R₂═H; or (b) R═F; R₁═CH₃O; OH;R₂═H; and

[0018] X⁻ is the monovalent anion of a pharmacologically acceptableacid.

[0019] What is meant by pharmacological acceptable salts of compounds offormula (II) are any of its salts with an acid that does not give riseto unwanted toxic or side effects. Such acids are well known topharmacologists and to experts in pharmacy and pharmaceuticaltechnology.

[0020] Examples of such salts—though not exclusively these—are chloride,bromide, orotate, acid aspartate, acid citrate, acid phosphate, fumarateand acid fumarate, lactate, maleate and acid maleate, acid oxalate, acidsulphate, glucose phosphate, tartrate and acid tartrate.

[0021] FDA approved salts are listed in Int. J. of Pharm. 33 (1986),201-217, which is incorporated herein for reference purposes.

[0022] Preferred examples of specific compounds as per the inventiondescribed herein are:

[0023] S(−)-2-amino-6-fluoro-7-hydroxytetraline hydrochloride (ST 1237);

[0024] R-(+)-2-amino-6-fluoro-7-hydroxytetraline hydrochloride (ST1238);

[0025] (R,S)-2-amino-5,6-difluoro-7-methoxytetraline hydrochloride (ST1269);

[0026] (R,S)-2-amino-6-fluoro-7-methyltetraline hydrochloride (ST 1275);

[0027] (R,S)-2-amino-7-fluoro-6-hydroxytetraline hydrochloride (ST1267);

[0028] (R,S)-7-acetyl-2-amino-6-methyltetraline hydrochloride (ST 1274);

[0029] (R,S)-2-amino-7-fluoro-6-methoxytetraline hydrochloride (ST1262).

[0030] The process for preparing the compounds according to theinvention described herein either as free bases or as pharmacologicallyacceptable salts is reported in the following reaction schemes:

[0031] With reference to the above reaction schemes, the followingexamples, wherein X═Cl⁻, illustrate the invention without limiting itexclusively to these.

EXAMPLE 1 Scheme 1

[0032] Preparation of S(−)-2-amino-6-fluoro-7-hydroxytetralinehydrochloride (ST 1237) 8a

[0033] a) Preparation of S(−)-trifluoroacetyl-aspartic anhydride 1a

[0034] L-Aspartic acid (100 g; 0.75 moles) was suspended intrifluoroacetic acid (300 mL), the resulting suspension was kept understirring and cooled to −20° C. in an ice/salt bath. Trifluoroaceticanhydride (300 mL; 2.16 moles) was slowly added thereto under stirring.At the end of the addition the resulting mixture was cautiously refluxedat 45° C. overnight.

[0035] When the reaction ended, the solution was brought to dryness inan evaporator and the solid residue was washed three times with hexaneunder stirring, each time removing the hexane by decantation; theresidue was again completely brought to dryness. Finally, the residuewas triturated under stirring with hexane-ethyl ether, the resultingmixture was filtered and the residue was dried under vacuum. 150 g ofcompound 1a were obtained (yield 95%).

[0036] M.P.: 140-142° C.

[0037] [α]D=−40.7 (c=1% methyl alcohol)

[0038]¹H-NMR(DMSOd₆), Varian 300 MHz, δ(p.p.m.): 2.85-3.,3 (2H,m,CH ₂);4.95-5.1(1H,m,CHNH); 9.6-9.8 (1H,bd,CHNHCOCF₃).

[0039] b) Preparation of S(+)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-(N-trifluoro-acetyl)-aminobutanoicacid 3a

[0040] S(−)-trifluoroacetyl-aspartic anhydride (150 g; 0.712 moles) wassuspended in 2-fluoroanisole (300 mL; 2.67 moles), the resulting mixturewas vigorously stirred and then anhydrous aluminium chloride (240 g;1.57 moles) was slowly added in small portions. When the addition wascompleted, the mixture was kept under vigorous stirring at 40-45° C. for24 h.

[0041] Anhydrous CH₂Cl and a further 60 g of AMCl₃ were added and thereaction mixture was kept under stirring for a further 48 h.

[0042] The solid residue was then treated with one litre of CH₂Cl₂ bygrinding it under stirring. The methylene chloride containing the excessfluoroanisole was separated. The solid residue was filtered off andadded portionwise to 2 litres of 6 M HCl kept under vigorous stirring.On completing the addition, the mixture was kept under stirring for 30min. The acid phase was then repeatedly extracted with ethyl ether. Thecombined ether phases were washed with water, dried over anhydroussodium sulphate and then brought to dryness. A raw solid residue wasobtained which was crystallised by 1:1 AcOEt/hexane. 188 g of compound3a were obtained (yield 78%).

[0043] M.P.: 113-115° C.

[0044] [α]D+27.5 (c=1% methyl alcohol)

[0045]¹H-NMR(CD₃OD), Varian 300 MT,Hz, δ (p.p.m.): 3.6 (2H,m,CH ₂NH);3.96(3H,S,PhOCH ₃); 4.88-5.01 (1H,m,CH₂CH ₂NH); 7.18-7.22 (1H,t,Ar);7.7-7.8(1H,dd,Ar); 7.82-7.9(1H,bd,Ar).

[0046] c) Preparation ofS(+)-4-(3-fluoro-4-methoxyphenyl)-2-(N-trifluoroacetyl)-aminobutanoicacid 4a

[0047] Compound 3a (100 g; 0.297 moles) was dissolved intrifluoro-acetic acid (500 mL). The resulting solution was cooled to 0°C. and triethylsilane (300 mL; 1.89 moles) slowly added. When theaddition was complete, the mixture was slowly brought to its boilingpoint and kept at boiling temperature for 4 h.

[0048] The mixture was then brought to complete dryness in anevaporator; the residue was washed twice with ethyl ether, each timebringing the mixture to dryness to completely eliminate thetrifluoracetic acid. The oily residue thus obtained was cooled to −20°C. in an ice/salt bath and then treated under stirring with an NaHCO₃saturated solution whose pH had been adjusted to 10 with 4N NaOH.

[0049] The final alkaline phase was cautiously acidified to pH 3 with 6NHCl, at 0° C. A precipitate was obtained which was repeatedly extractedwith CH₂Cl₂. The combined organic extracts were washed in a small amountof water, dried over anhydrous Na₂SO₄ and brought to dryness. The oilyresidue was dissolved in a small amount of ethyl acetate andprecipitated with hexane under stirring. The mixture was kept understirring overnight, filtered and the residue was dried. 72 g of compound4a were obtained (yield 75%).

[0050] M.P.: 113-115° C.

[0051] [α]D=+11.3 (c=1% methyl alcohol) analysis: conforms to standards.

[0052]¹H-NMR(CDCl₃), Varian 300 MHz, δ(p.p.m.): 2.0-2.18 (1H,m,CHHCHNH);2.22-2.36 (1H,m,CHHCHNH); 2.6-2.7(2H,t,PhCH ₂CH₂); 3.84(3H,S,PhOCH ₃);4.6-4.7(1H,m,CH₂CHNH); 6.78(1H,bd, CHNHCOCF₃); 6.8-6.92(2H,m,Ar).

[0053] d) Preparation ofS(−)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methoxy-1-tetralone 5a

[0054] Compound 4a (70 g; 0.217 moles) was dissolved in anhydrousmethylene chloride (1400 mL). The resulting mixture was cooled to 0° C.in an ice bath and then phosphorus pentachloride (70 g; 0.336 moles) wasslowly added. At the end of the addition, the mixture was kept understirring at 0° C. for about 2 h, and then cooled to −20° C. Aluminiumchloride (56 g; 0.42 moles) was added to the mixture in small portions.

[0055] Following the addition, the mixture was kept for 2 h at roomtemperature and then cautiously heated to boiling point and kept atboiling temperature for about 6 h.

[0056] The mixture was then cooled to 0° C. and crushed ice (about 300mL) was added portionwise under stirring to destroy the excessreactants. The mixture was extracted three times with CH₂Cl₂. Thecombined organic phases were dried over anhydrous Na₂SO₄ and brought todryness. A yellowish solid was obtained which was dissolved in a smallvolume of ethyl acetate and then precipitated with hexane. 40 g ofcompound 5a were obtained 0.15 (yield 60%).

[0057] M.P.: 184-185° C.

[0058] [α]_(CD)=−55.4 (c=1% methyl alcohol)

[0059]¹H-NMR (CDCl₃), Varian 300 MHz, (p.p.m.): 1.83-2.2 (1H,m,CHHCHNH);2.8-2.88 (1H,m,CHHCHNH); 2.9-3.0 (1H,mCHHCH₂); 3.15-2.26 (1H,m,CHHCH₂);3.92(3H,S,PhOCH ₃); 4.53-4.62 (1H,m,CH₂CHNHCOCF₃); 6.88 (1H,d,Ar.); 7.57(1H,d,Ar.); 7.43 (1H,bs,CHNHCOCF₃).

[0060] e) Preparation ofS(−)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methoxy-tetraline 6a

[0061] Compound 5a (40 g; 0.131 moles) was suspended in boroetheratetrifluoride (340 mL) at 0° C. Triethylsilane (90 mL; 0.567 moles) wasadded to the suspension at 0° C., and the suspension was kept understirring for 4 days at room temperature. At the end of the reaction asaturated solution of NaHCO₃ (pH 8-9) was added to the reaction mixtureand the aqueous phase was extracted four times with CH₂Cl₂. The combinedorganic phases were washed with water, dried over anhydrous Na₂SO₄,filtered and brought to dryness.

[0062] The raw compound thus obtained was recrystallised from isopropylether. 30 g of compound 6a were obtained (yield 78%).

[0063] M.P.: 45-47° C.

[0064] [α]_(D)=80 (c=1% methyl alcohol)

[0065]¹H-NMR(CDCl₃), Varian 300 MHz, δ (.p.m.): 1.78-1.9 (1H,m,CHHCNNH);2.0-2.15 (1H,m,CHHCHNH); 2.6-2.72 (1H,dd,PhCHHCHNH); 2.73-2.9(2H,m,PhCHHCHNH,PhCHHCH₂); 3.03-3.15 (1H,dd,PhCHHCH₂) 4.2-4.35(1H,m,CHNH); 6.38 (1H,bd,CHNHCOCF₃); 6.6 (1H,d,Ar); 6.8 (1H,d,Ar).

[0066] I) Preparation of S(−)-2-amino-6-fluoro-7-methoxytetralinehydrochloride 7a

[0067] Compound 6a (30 g; 0.13 moles) was dissolved in methanol (225 mL)and water (225 mL) containing K2CO₃ (54 g; 0.391 moles).

[0068] The resulting solution was refluxed under stirring for 3 hours.

[0069] Methanol was removed under vacuum and a further 100 mL of wateradded to the solution.

[0070] The aqueous phase was repeatedly extracted with CH₂Cl₂. Thecombined organic phases were dried over anhydrous Na₂SO₄, filtered andbrought to dryness. The oily solid thus obtained was dissolved in ethylether acidified with HCl (15% solution in ethanol) and the solidprecipitate was filtered off and redissolved in methanol, decolouredwith activated charcoal, filtered, concentrated under vacuum and finallycrystallised with n-propanol.

[0071] Crystallisation was repeated twice giving 12.6 g of compound 7(Yield 53%).

[0072] M.P.: 263-265° C.

[0073] [α]_(D)=52.5 (c=1% H₂O)

[0074]¹H -NMR (CDCl₃), Varian 300 MHz, δ ppm): 1.6-1.8 (1H, m,CHHCHN+);2.0-2.15(1H,m,CHHCHN+); 2.6-2.75 (3H,m,PhCHHCHN+, PhCH ₂CH₂); 2.95-3.05(1H,DD,PhCHHCHN+); 3.45-3.55 1H, m, CHN+); 6.7-6.7(2H,m,Ar).

[0075] g) Preparation of S(−)-2-amino-6-fluoro-7-hydroxytetralinehydrochloride (ST 1237) 8a

[0076] A solution of S(−)-2-amino-6-fluoro-7-methoxytetralinehydrochloride 7a (3 g; 0.13 moles) in 20 mL of hydrobromic acid (47%aqueous solution) was kept at reflux temperature overnight. At the endof refluxing the solution was concentrated and brought to dryness undervacuum. The residue thus obtained was repeatedly washed under stirringwith acetone and filtered off, redissolved in a 1:1 water/methanolmixture and eluted through a column containing 60 mL of Amberlyst A 21resin, activated in basic form.

[0077] The eluate was acidified with 2 N hydrochloric acid and thenconcentrated to dryness under vacuum; the residue thus obtained waswashed with acetone, filtered off and again dissolved in 1:1water/methanol and eluted through a column containing 60 mL of AmberlystA 21 resin activated in acid form.

[0078] The eluate was decoloured with activated charcoal, filteredthrough celite and concentrated in a small volume. Acetone was addedthereto obtaining a precipitate that was filtered off and dried in theoven under vacuum. 2.2 g of compound 8a were obtained (yield 78%).

[0079] M.P.: 259-261° C.

[0080] [α]_(D)=−55.4 (c=1% H₂O)

[0081]¹H-NMR (D₂O), Varian 300 MHz, δ (p.p.m.): 1.6-1.8 (1H, m,CH₂CHHCCHN⁺); 2.0-2.1 (1H, m, CH₂CHHCHN⁻); 2.5-2.7 (3H, m, PhCH ₂CH₂),PhCHHN⁺); 2.85-3.0 (1H, m, PhCHHN⁻); 3.4-3.55 (1H, m, CHN+); 6.55-6.8(2H, 2d, Ar.).

EXAMPLE 2 Scheme 1

[0082] a) Preparation of R (+)-2-amino-6-fluoro-7-hydroxytetralinehydrochloride (ST 1238) 8b

[0083] a) Preparation of R(+)-trifluoroacetyl Astartic 1b

[0084] The preparation is basically similar to that utilised forS(−)-trifluoro-acetyl-aspartic 1a using D(−)aspartic acid as thestarting product (yield 86%).

[0085] M.P.: 142-144° C.

[0086] [α]_(D)=+40.0 (c=1% methyl alcohol)

[0087]¹H-NMR: in accordance with and coinciding with that obtained withproduct 1a.

[0088] b) Preparation ofR(−)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-(N-trifluoroacetyl)aminobutanoicAcid 3b

[0089] The preparation is basically similar to that utilised forS(+)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2-(N-trifluoroacetyl)aminobutanoic acid 3a, using anhydride 1b as the starting material(yield 57%).

[0090] M.P.: 86-88° C.

[0091] [α]_(D)=−28.0 (c=1% methyl alcohol)

[0092]¹H-NMR: in accordance and coinciding with that obtained withproduct 3a.

[0093] c) Preparation ofR(−)-4-(3-fluoro-4-methoxyphenyl)-2-(N-trifluoroacetyl)aminobutanoicAcid 4b

[0094] The preparation is basically similar to that utilised forS(+)-4-(3-fluoro-4-methoxyphenyl)-2-(N-trifluoroacetyl)-aminobutanoicacid 4a using acid 3b as the starting material yield 65%).

[0095] M.P.: 110-112° C.

[0096] [α]_(D)=−11.2 (c=1% methyl alcohol)

[0097]¹H-NMR: in accordance and coinciding with that obtained withproduct 4a.

[0098] d) Preparation ofR(+)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methoxy-1-tetralone Acid 5b

[0099] The preparation is basically similar to that utilised forS(−)-2-(N-trifluoroacetyl)-amino-6-fluoro-7-methoxy-1-tetralone acid 5ausing anhydride 4b as the starting material (yield 84%).

[0100] M.P.: 185-186° C.

[0101] [α]_(D)=+66.0 (c=1% methyl alcohol)

[0102]¹H-NMR: in accordance and coinciding with that obtained withproduct 5a.

[0103] e) Preparation ofR(+)-2-(N-trifluoroacetyl)-amino-6-fluoro-7-methoxytetraline Acid 6b

[0104] The preparation is basically similar to that utilised for S(−)-2-(N-trifluoroacetyl)-amino-6-fluoro-7-methoxytetraline acid 6a usingtetralone 5b as the starting material (yield 47%).

[0105] M.P.: 145-147° C.

[0106] [α_(D)]=+92.0 (c=1% methyl alcohol)

[0107]¹H-NMR: in accordance and coinciding with that obtained withproduct 6a.

[0108] f) Preparation of R(+)-2-amino-6-fluoro-7-methoxytetralinehydrochloride 7b

[0109] The preparation is basically similar to that utilised forS(−)-2-amino-6-fluoro-7-methoxytetraline hydrochloride 7a usingtetraline 6b as the starting material (yield 64%).

[0110] M.P.: 260-262° C.

[0111] [α]_(D)=+48.5 (c=1% H²⁰)

[0112]¹H-NMR: in accordance and coinciding with that obtained withproduct 7a.

[0113] g) Preparation of R(+)-2-amino-5-fluoro-7-hydroxytetralinehydrochloride (ST 1238) 8b

[0114] The preparation is basically similar to that utilised forS(−)-2-amino-5-fluoro-7-hydroxytetraline hydrochloride (ST 1237) 8ausing tetraline hydrochloride 7b as the starting material (yield 78%).

[0115] M.P.: 260-262° C. P [α]_(D)=+55.0 (c=1% H₂O)

[0116]¹H-NMR (D₂O), Varian 300 MHz, δ (p.p.m.):

[0117] 1.6-1.8(1H,m,CH₂CHHCHN+); 2.0-2.1 (1H,m,CH₂CHHCHN+);2.5-2.7(3H,m,PhCH ₂CH₂)PhCHHCHN+); 2.85-3.0(1H, m, PhCHHCHN);3.4-3.55(1H,m,CHN⁺); 6.55-6.8(2H,2d,Ar.).

EXAMPLE 3 Scheme 1

[0118] Preparation of (R,S)-2-amino-5,6-difluoro-7-methoxytetralinehydrochloride (ST 1269) 7c

[0119] a) Preparation of (R,S)-trifluoroacetyl-aspartic Anhydride 1c

[0120] The preparation is basically similar to that utilised forS(−)-trifluoroacetyl-aspartic anhydride 1a using D,L-aspartic acid asthe starting product (yield 96%).

[0121] M.P.: 133-134° C.

[0122] 1HNMR: in accordance and coinciding with that obtained withproduct 1a.

[0123] a′) Preparation of 2.3-difluoroanisole 2

[0124] 20 g (0.154 moles) of 2.3-difluorophenol were salified by shakingthe product at room temperature in a solution of 6.24 g of NaOH in 60 mLof water to completely dissolve it.

[0125] To the solution cooled to about 10° C., 14.4 mL of dimethylsulphate, were slowly added; the solution was then heated to refluxtemperature and refluxed for 24 h.

[0126] The reaction mixture was brought to room temperature andextracted with methylene chloride; the organic phase was washed withwater, N sulphuric acid and again with water until a neutral pH wasobtained.

[0127] The solution was dehydrated with anhydrous sodium sulphate andthe solvent removed under vacuum to give 21 g of compound a′ as areddish oil which was analysed by NMR and utilised as it was (yield 94%on the raw material).

[0128]¹H-NMR (D₂O) Varian 300 MHz δ (p.p.m.): 3.9 (3H,S,PhOCH₃); 6.6-7.2(3H, m, aromatics).

[0129] b) Preparation of (R,S)-4-(23-difluoro-4-methoxyphenyl)-4-oxo-2(N-trifluoroacetyl)aminobutanoicAcid 3c

[0130] The preparation is basically similar to that utilised for S(+)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-2 (N-trifluoroacetyl) aminobutanoicacid 3a using anhydride 1c and 2.3-difluoroanisole as the startingproducts and 2 and 72 h as the reaction time instead of 48 h (yield23%).

[0131]¹H-NMR (D₂O) Varian 300 MHz δ (p.p.m.): 3.9 (3H,S,PhOCH ₃);6.6-7.2 (3H, m, aromatics).

[0132] c) Preparation of (R,S-4-(2.3-difluoro-4-methoxyphenyl)-2-(N-trifluoroacetyl)aminobutanoic acid 4c

[0133] The preparation is similar to that utilised forS(+)-4-(3-fluoro-4-methoxyphenyl)-2-(N-trifluoroacetyl) aminobutanoicacid 4a using acid 3c as the starting product (yield 76%).

[0134]¹H-NMR (CDCl₃), Varian 300 MHz, δ (p.p.m.): 2.0-2.2 (1H, m,CHHCHN+) 2.2-2.4 (1H,m,CHHCHCN); 2.6-2.8 (2H,t,PhCH ₂CH₂); 3.86(3H,S,PhOCH ₃); 4.6-4.72 (1H,bq, CH ₂CHNH); 6.6-6.7 (1H,bt,Ar);6.75-6.88 (2H,m,Ar,CHNHCOCF₃).

[0135] d) Preparation of(R,S)-2-(N-trifluoroacetyl)amino-5,6-difluoro-7-methoxy-1-tetralone 5c

[0136] The preparation is basically similar to that utilised forS(−)-(N-trifluoroacetyl)amino-6-fluoro-7-methoxy-1-tetralone 5a usingacid 4c as the starting product and 3 h at reflux after the addition ofaluminium chloride instead of 6 h as the reaction time (yield 26%).

[0137]¹H-NMR (CDCl3), Varian 300 MHz, δ (p.p.m.): 1.85-2.0 (1H, m,CHHCHN+) 2.84-3.07 (2H,m,CHHNH, PhCHHCH₂); 3.13-3.24 (1H,m,PhCHHCH₂);3.93 (1H,S,PhOCH ₃); 4.55-4.65 (1H,m, CH₂CHNH); 7.38-7.42 (1H,dd,Ar);7.43-(1H,bs,CHNHCOCF₃).

[0138] e) Preparation of(R,S)-2-(N-trifluoroacetyl)amino-5.6-difluoro-7-methoxytetraline 6c

[0139] The preparation is basically similar to that utilised forS(−)-(N-trifluoroacetyl)amino-6-fluoro-7-methoxytetraline 6a (example 1)using tetralone 5c as the starting product and 7 days instead of 4 asthe reaction time (yield 46%).

[0140]¹H-NMR (CDCl₃), Varian 300 MHz, δ (.p.m.): 1.75-1.9 (1H, m,CHHCHN+) 2.04-2.16 (2H,m,CHHCHNH); 2.6-2.9 (3H,m,PhCH ₂CHNH, PhCHHCH₂);3.05-3.15 (1H,dd,PhCHHCH₂); 3.84 (3H,s,PhOCH ₃); 4.2-4.33(1H,m,CHNHCOCF₃); 6.22 (1H,bs,CHNHCOCF₃); 6.9-6.94(1H,bd,Ar).

[0141] f) Preparation of(R,S)-2-amino-5.6-difluoro-7-methoxy-1-tetraline hydrochloride ST (1269)7c

[0142] The preparation is basically similar to that utilised forS(−)-2-amino-6-fluoro-7-methoxytetraline hydrochloride 7a usingtetraline 6c as the starting product and isopropanol as thecrystallisation solvent (yield 62%).

[0143] M.P.: decomposes at 210° C.

[0144]¹H-NMR (D₂O), Varian 300 MHz, δ (p.p.m.): 1.6-1.8(1H, m,CH₂CHHCHN+) 2.0-2.2 (1H,m,CH₂CHHCHN+, 2.5-2.9 (3H,m,PhCHHCHN+,PhCH₂CH₂); 2.9-3.1 (1H,m, PhCHCHN+); 3.4-3.6 (1H,m,CHN⁺); 6.5-6.6(1H,d,Ar).

EXAMPLE 4 Scheme 11

[0145] Preparation of (R,S)-2-amino-6-fluoro-7-methyltetralinehydrochloride (ST 1275) 7d

[0146] a) Preparation of (R,S)-trifluoroacetyl Aspartic Anhydride 1c(See example 3)

[0147] b) Preparation of(R,S)-4-(3-fluoro-4-methyl-Phenyl)-4-oxo-2-(N-tri-fluoroacetyl)aminobutanoicAcid 3d

[0148] The preparation is basically similar to that utilised forS(+)-4-(3-fluoro -4-methoxyphenyl)-4-oxo-2-(N-trifluoroacetyl)aminobutanoic acid 3a using fluorotoluene as the starting product and 72h instead of 48 h as the reaction time (yield 36%).

[0149]¹H-NMR (CDCl₃) Varian 300 MHz, δ (p.p.m.): 2.15 (3H, d, PhCH ₃);3.35-3.42 (1H,dd,CHHCHNH); 3.5-3.6(1H,dd,CHHCHNH); 4.68-4.76(1H,m,CH₂CHNH); 6.85-6.95 (1H,t,Ar); 7.55-7.65 (2H,m,Ar);8.0-8.1(1H,bd,CHNHCOCF₃).

[0150] c) Preparation of(R,S)-4-(3-fluoro-4-methyl-phenyl)-2-(N-trifluoroacetyl)aminobutanoicAcid 4d

[0151] The preparation is basically similar to that utilised forS(+)-4-(3-fluoro-4-methoxyphenyl)-2- (N-trifluoroacetyl) aminobutanoicacid 4a using acid 3d as the starting product (yield 52%).

[0152]¹H-NMR (CDCl₃) Varian 200 MHz, δ (p.p.m.): 2.15 (3H, d, PhCH ₃);2.0-2.4 (2H,dd,CH ₂CHNH); 2.5-2.7(2H,t,PhCH₂CH₂); 4.5-4.7(1H,bq,CH₂CHNH); 6.6-6.7 (1H,m,Ar); 6.75-6.95 (2H,m,Ar); 7.35-7.5(1H,bd,CHNHCOCF₃).

[0153] d) Preparation of(R,S)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methyl-1-tetralone 5d

[0154] The preparation is basically similar to that utilised forS(−)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methoxy-1-tetralone 5a usingacid 4d as the starting product and 1 h at reflux instead of 2 h at roomtemperature, and, after the addition of aluminium chloride, 6 h atreflux as the reaction time (yield 80%).

[0155]¹H-NMR (CDCl₃) Varian 300 MHz, δ (p.p.m.): 1.83-2.0 (1H, d,CHHCHNH); 2.3-(3H,d,PhCH ₃); 2.8-2.9(1H,m,CHHCHNH); 2.92-3.03(1H,m,CHHCH₂); 3.13-3.25(1H,m,CHHCH₂); 4.53-4.62 (1H,m,CH₂CHNHCOCF₃);7.2(1H,d,Ar); 7.6(1H,d,Ar); 7.45(1H,bs,CHNHCOCF₃).

[0156] e) Preparation of(R,S)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methyl-tetraline 6d

[0157] The preparation is analogous to that utilised forS(−)-2-(N-trifluoroacetyl)amino-6-fluoro-7-methoxytetraline 6a, usingtetralone 5d as the starting product (yield 60%).

[0158]¹H-NMR (CDCl₃) Varian 300 MHz, δ (p.p.m.): 1.75-1.9 (1H, m,CHHCHNH); 2.0-2.15 (1H,m,CHHCHNH); 2.2(3H,s,PhCH ₃); 2.6-2.7(1H,dd,PhCHHCHNH); 2.7-2.9 (2H,m,PhCHHCHNH,PhCHHCH₂);3.03-3.15(1H,dd,PhCHHCH₂) 4.25-4.35 (1H,m,CHNH); 6.2 (1H,b,s,NHCOCF₃);6.7(1H,d,Ar); 6.9 (1H,d,Ar).

[0159] f) Preparation of (R,S)-2-amino-6-fluoro-7-methyltetralinehydrochloride (ST 1275) 7d

[0160] The preparation is basically similar to that utilised forS(−)-2-amino-6-fluoro-7-methoxytetraline hydrochloride 7a, usingtetraline 6d as the starting product (yield 67%). M.P.: decomposes at230° C.

[0161]¹H-NMR (CD₃OD) Varian 300 MHz, δ (p.p.m.): 1.7-1.9 (1H, m,CH₂CHHCHN⁺); 2.15-2.25 (1H,m,CH₂CHHCHN⁺); 2.19(3H,S,PhCH ₃); 2.7-2.9(3H,m,PhCHNH⁺,PhCH ₂CH₂); 3.05-3.6(1H,m,PhCHHCHN+); 3.45-3.6(1H,m,CHNH₃+); 6.75-6.8 (1H,d,Ar); 6.95-7.0 (1H,d,Ar).

EXAMPLE 5 Scheme 2

[0162] Preparation of (R,S)-2-amino-6-methoxy-7-fluorotetralinehydro-chloride (ST 1262) 6a

[0163] a) Preparation of4-(6-methoxy-7-fluoro-henyl)-3-carbomethoxy-3-butanoic acid 1a

[0164] 9.4 g (0.061 moles) of 3-fluoro-p-anisaldheyde and 10 g (0.068moles) of dimethyl succinate were dissolved in 15 mL of anhydrousmethanol. The solution thus obtained was added dropwise at roomtemperature to a previously prepared solution of sodium methoxide 1.66 g(0.073 moles). The reaction mixture was refluxed for 3 h in a nitrogenatmosphere, then cooled and concentrated at half volume under vacuum.

[0165] The solution thus obtained was acidified with 2N HCl, cooling itin an ice bath, and then diluted with water until precipitation of theproduct occurred. The precipitate was filtered off and dissolved in asaturated solution of sodium hydrogen carbonate. The aqueous solutionwas repeatedly shaken with ethyl ether and re-acidified with 2N HCl andcooled in an ice bath.

[0166] The product was repeatedly extracted from the aqueous solution,with anhydrous sodium sulphate, and the solvent removed under vacuumobtaining a solid product which was crystallised with an ethylacetate/n-hexane mixture, brought to dryness to give 5.5 g of acid 1a(yield 33%). M.P.: 141-144° C.

[0167]¹H-NMR (CDCl₃), Varian 300 MHz, δ (p.p.m.): 3.55 (2H,s,CH ₂COOH);3.83 (3H,s,COOCH ₃); 3.9(3H,s,PhOCH ₃); 6.95-7.2 (3H,m,Ar); so 7.8(1H,s,CH═C).

[0168] b) Preparation of(R,S)-4-(6-methoxy-7-fluorophenyl)-3-carbomethoxybutanoic acid 2a

[0169] 2 g (0.0075 moles) of4-(6-methoxy-7-fluorophenyl)-3-carbomethoxy-3-butanoic acid weredissolved in 80 mL of ethyl acetate and then hydrogenated in Parrapparatus with 200 mg of palladium on charcoal at 5.5 p.s.i. hydrogenpressure for 1.5 h. The solution was filtered through celite and thecatalyst and solvent removed under vacuum to give 1.9 g of oil whichspontaneously crystallise (yield 93%).

[0170]¹H-NMR (CDCl₃), Varian 200 MHz, δ (p.p.m.) 2.3-2.45(1H,m,CHCOOCH₃); 2.5-2.75 (2H, m, CH ₂COOH); 2.8-3.1 (2H,m,PhCH ₂); 3.6(3H,s,COOCH ₃; 3.8 (3H,s,PhOCH ₃); 6.75-6.9(3H,m,Ar)

[0171] c) Preparation of(R,S)-6-methoxy-7-fluoro-4-oxo-1,2,3,4-tetrahydro-2-naphthoic acid ethylester 3a

[0172] 5.6 g (0.021 moles) of(R,S)-4-(6-methoxy-7-fluorophenyl)-3-carbomethoxy-buzanoic acid 2a weredissolved in 100 mL of anhydrous methylene chloride; 5 g (0.024 moles)of phosphorus pentachloride were added, and the temperature wasmaintained at 0° C. for 45 min. The temperature was brought to −10° C.and 3.6 g (0.027 moles) of aluminium chloride were added to thesolution; the temperature was left to rise to 20° C. in 40 min, and thenthe solution was heated to reflux temperature for 1 h.

[0173] The solvent was evaporated under vacuum; 100 mL of cold waterwere added to the suspension which was extracted 3 times with 150 mL ofethyl acetate; the organic solution was dehydrated over anhydrous sodiumsulphate and the solvent removed under vacuum to give 4.3 g of solidproduct (yield 81%).

[0174]¹H-NMR (CDCl₃), Varian 200 MHz, δ (p.p.m.) 2.3-2.45(1H,m,CHCOOCH₃); 2.5-2.75 (2H, m, CH ₂COOH); 2.8-3.1 (2H,m,PhCH ₂); 3.6(3H,s,COOCH ₃; 3.8 (3H,s,PhOCH ₃); 6.75-6.9(3H,m,Ar)

[0175] d) Preparation of(R,S)-6-methoxy-7-fluoro-1.2.3.4-tetrahydro-2-napthoic acid methyl ester4a

[0176] 6 g (0.024 moles) of the(R,S)-6-methoxy-7-fluoro-4-oxo-1,2,3,4-tetrahydro-2-naphthoic acidmethyl ester 3a were dissolved in 100 mL of a mixture composed ofanhydrous methanol and 50 mL of glacial acetic acid; the solution wasplaced in a Parr apparatus with 800 mg of palladium over charcoal at 50p.s.i. hydrogen pressure for 4 h.

[0177] The catalyst was filtered off through celite and the solventremoved under vacuum, obtaining 5.5 g of solid product (yield 98%).

[0178]¹H-NMR (CDCl₃), Varian 300 MHz, δ (p.p.m.): 1.75-1.9(1H,m,CHHCHCOOCH₃); 2.1-2.22(1H,m,CHHCHCOOCH₃); 2.6-2.8 (3H,m,PhCH₂CHCOOCH₃, CHCOOCH₃); 2.9 (2H,d,PhCH ₂CH₂); 3.7 (3H,s,COOCH ₃); 3.83(3H,s,PhOCH ₃); 6.62 (1H,d,Ar); 6.78 (1H,d,Ar).

[0179] e) Preparation of(R,S)-6-methoxy-7-fluoro-1,2,3,4-tetrahydro-2-naphthoic acid 5a

[0180] 5.2 g (0.022 moles) of(R,S)-6-methoxy-7-fluoro-1,2,3,4-tetrahydro-2-naphthoic acid 4a weresuspended in a solution composed of 2.2 g of potassium carbonate in 50mL of 50% aqueous solution of methanol; the resulting solution wasrefluxed for 1 h.

[0181] The methanol was removed under vacuum and the solution dilutedwith 150 mL of water and washed with ethyl ether; the aqueous solutionwas acidified with 12 N HCl.

[0182] The precipitate thus obtained was filtered off and dried to give4.8 g of product (yield 97%).

[0183]¹H-NMR (CDCLs), Varian 300 MHz, δ (p.p.m.): 1.8-1.95(1H,m,CHHCHCOOCH₃); 2.1-2.25 (1H,m,CHHCHCOOCH₃); 2.65-2.85(3H,m,PhCH₂CHCOOCH₃, CHCOOCH₃); 2.95(2H,d,PhCH ₂CH₂); 3.82 (3H,s,PhOCH ₃);6.6(1H,d,Ar);6.8(1H,d,Ar).

[0184] f) Preparation of (R,S)-2-amino-6-methoxy-7-fluorotetralinehydro-chloride (ST 1262) 6a

[0185] 4.11 g (0.018 moles) of(R,S)-6-methoxy-7-fluoro-1,2,3,4-tetrahydro-2-naphthoic acid 5a weredissolved in 9 mL of thionyl chloride under a nitrogen atmosphere andthe solution was heated to 60° C. for 4 h; toluene was then added andthe solution repeatedly extracted under vacuum.

[0186] A green oil was obtained which was dissolved in 12 mL ofanhydrous acetone and added dropwise to a solution of sodium azide 1.75g (0.024 moles) in 12 mL of water, cooling the reaction mixture to 0° C.

[0187] The mixture was left to react under stirring for 30 min leavingthe temperature to rise to 20° C. The mixture was again cooled to 0-5°C. and 150 mL of water were added.

[0188] The precipitate thus obtained was brought to dryness undervacuum, obtaining 3.9 g of acid azide.

[0189] The product thus obtained was dissolved in 12 mL of toluene andheated for 30 min to 100° C.; the solvent was removed, obtaining a denseoil to which 10 mL of anhydrous benzyl alcohol were added, whereupon thesolution was again heated at 100° C. for 6 h.

[0190] The solution was cooled to 5° C. overnight; the precipitate thusobtained was then filtered off and brought to dryness, obtaining 4.7 gof carbobenzoxy derivative.

[0191] The product was placed in 350 mL of anhydrous ethanol anddissolved by heating slightly, and acidified with about 2 mL ofconcentrated HCl; 500 mg of palladium over charcoal were added and themixture thus obtained was placed in Parr apparatus and hydrogenated for5 h at 50 p.s.i. hydrogen pressure.

[0192] The catalyst was filtered off over celite and repeatedly washedwith heated ethanol; the solvent was removed under vacuum and the solidthus obtained was crystallised with an ethanol/ethyl ether mixture(yield 58%). M.P.: decomposes at 230° C.

[0193]¹H-NMR (DMSOd₆), Varian 300 MHz, δ (p.p.m.): 1.6-1.8(1H,m,CHHCHN⁺); 2.0-2.2 (1H,m,CHHCHN⁺); 2.6-3.0(4H,m,PhCH ₂CH₂CH₂,PhCH₂CHNN+); 3.8 (3H,s,OCH ₃); 6.8-7.0(2H,2d,Ar)

EXAMPLE 6 Scheme 21

[0194] g) Preparation of (R,S)-2-amino-6-hydroxy-7-fluorotetralinehydro-chloride (ST 1267) 7

[0195] 0.6 g (0.0026 moles) of (R,S)-2-amino-6-methoxy-7-fluorotetralinehydrochloride 6a were suspended in 8 mL of hydrobromic acid 47% solutionin water and then heated to 130° C. overnight.

[0196] Water was removed by evaporation under vacuum; the dark solidthus obtained, dissolved in 50% aqueous solution of methanol, was elutedthrough a column of 20 mL of A-21 resin activated in a basic form.

[0197] The eluted solution was acidified to pH 2 with 3N hydrochloricacid, concentrated under vacuum and eluted through a column of 20 mL ofA-21 resin activated in hydrochloride form.

[0198] The solvent was completely removed under vacuum.

[0199] The solid thus obtained was treated with acetone, filtered offand crystallised from methanol by addition of ethyl ether; 350 mg ofproduct were obtained (yield 62%). M.P.: decomposes at about 200° C.

[0200]¹H-NMR, (CD₃OD), Varian 300 MHz, δ (p.p.m.): 1.7-1.9(1H,m,CHHCHN+); 2.1-2.3 (1H,m,CHHCHN+); 2.7-3.1(4H,m,PhCH ₂CH₂; PhCH₂CHN⁺); 3.4-3.6 (1H,m,CHN+); 6.6-6.85(2H,2d,Ar).

EXAMPLE 7 Scheme 2

[0201] Preparation of (R,S)-2-amino-6-methyl-7-acetyltetralinehydro-chloride (ST 1274) 10

[0202] a) Preparation of 4-(6-methylphenyl)-3-carbomethoxy-3-butanoicacid 1b

[0203] The preparation is basically similar to that utilised for4-(6-methoxy-7-fluorophenyl)-3-carbomethoxy-3-butanoic acid 1a, usingp-tolualdehyde as the starting product, 3 h as the reaction time atreflux, and a cyclohexane/ethyl acetate mixture as the crystallisa-tionsolvent yield 27%).

[0204]¹H-NMR(CDCl₃); Varian 200 MHz, δ (p.p.m.): 2.35 (3H,s,PhCH ₃);3.58 (2H,s,CH ₂COOH); 3.83 (3H,s,COOCH ₃); 7.15-7.3 (4H,m, Ar); 7.87(1H,s,CH═C).

[0205] b) Preparation of 4-(6-methylphenyl)-3-carbomethoxy-3-butanoicacid 2b

[0206] The preparation is basically similar to that utilised for4-(6-methoxy-7-fluorophenyl)-3-carbomethoxy-3-butanoic acid 2a, usingacid 1b as the starting product, and 2.5 h as the hydrogenation time(yield 94%).

[0207]¹H-NMR (CDCl₃), Variar. 200 MHz, δ (p.p.m.): 2.23 (1H,s,PhCH ₃);2.28-2.45(1H,m,CHCOOCH₃); 2.55-2.75 (2H,m,CH ₂COOH); 2.9-3.1 (2H,m,PhCH₂); 3.62 (3H,s,COOCH ₃); 6.9-7.1 (4H,m,Ar)

[0208] c) Preparation of(R,S)-6-methyl-4-oxo-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester 3b

[0209] The preparation is basically similar to that utilised for(R,S)-6-methoxy-7-fluoro-4-oxo-1,2,3,4-tetrahydro-2-naphthoic acidmethyl ester 3a, using acid 2b as the starting product (yield 94%).

[0210]¹H-NMR (CDCl₃), Varian 200 MHz, δ (p.p.m.): 2.35 (3H,s,PhCH ₃);2.7-2.9(2H, m, PhCH ₂); 3.1-3.2 (3H,m,PhCOCH ₂,CHCOOCH₃); 3.7(3H,s,COOCH ₃); 7.1-7.35 (2H,m,Ar); 7.8 (1H,s,Ar).

[0211] d) Preparation of (R,S)-6-methyl-1,2,3,4-tetrahydro-2-naphthoicacid methyl ester 4b

[0212] The preparation is basically similar to that utilised for(R,S)-6-methoxy-7-fluoro-1,2,3,4-tetrahydro-2-naphthoic acid methylester 4a, using methyl ester 3b as the starting product (yield 94%).

[0213]¹H-NMR (CDCl₃), Varian 200 MHz), δ (p.p.m.): 1.7-1.95(1H,m,CHHCHCOCCl₃); 2.1-2.3 (1H,m, CHHCHCOOCH₃); 2.3 (3H,s,PhCH ₃);2.6-2.85 (3H,m,PhCH ₂CHCOOCH₃, CHCOOCH₃); 2.9-3.0 (2H,d,PhCH ₂CH₂); 3.72(3H,s,COOCH ₃); 6.85-7.1 (3H,m,Ar)

[0214] h) Preparation of(R,S)-6-methyl-7-acetyl-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester8

[0215] 3.8 g (0.0186 moles) of(R,S)-6-methyl-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester 4b weredissolved in 30 mL of methylene chloride; 5.2 g of aluminium chloridewere added to the solution cooled to 5° C. under a nitrogen atmosphereand 1.6 mL of acetyl chloride were added dropwise at the sametemperature under stirring.

[0216] The reaction mixture was left to react at room temperature for1.5 h, whereupon the mixture was cooled by adding 100 mL of cold watervery slowly under stirring. The solution was repeatedly extracted with100 mL (total volume) of methylene chloride and washed repeatedly withcold water.

[0217] The organic phase was anhydrified with anhydrous sodium sulphate,and the solvent removed under vacuum obtaining a dark solid, which wasdried giving 3.8 g of raw product that was purified by silica gel columnchromatography (50 mL), using n-hexane/ethyl acetate 8:2 as the solvent.

[0218] The solvent was removed under vacuum obtaining 1.8 g of product(yield 40%).

[0219]¹H-NMR (CDCl₃), Varian 300 MHz, δ (p.p.m.): 1.78-2.0(1H,m,CHHCHCOCOOCH₃); 2.1-2.3 (1H,m,CHHCHCOOCH₃); 2.45 (3H,s,COCH ₃);2.55 (3H,s,PhCH ₃); 2.65-2.85 (3H,m,PhCH₂CHCOOCH₃, CHCOOCH₃); 2.95(2H,d,PhCH ₂CH₂); 6.95 (1H,s,Ar); 7.45 (1H,s,Ar).

[0220] i) Preparation of(R,S)-6-methyl-7-acetyl-1,2,3,4-tetrahydro-2-naphthoic acid 9

[0221] The preparation is basically similar to that utilised for(R,S)-6-methoxy-7-fluoro-1,2,3,4-tetrahydro-2-naphthoic acid 5, usingmethyl ester 8 as the starting product, 1.5 h at reflux temperature asthe reaction time and n-hexane/ethyl acetate as the crystallisationmixture (yield 82%).

[0222]¹H-NMR (CDCl), Varian 300 MHz, δ (p.p.m.): 2.78-2.92(1H,m,CHHCHCOOH); 2.1-2.25(1H,m,CHHCHCOOH); 2.4 (3H,s,COCH ₃); 2.5(3H,s,PhCH ₃); 2.7-2.9 (3H,m,PhCH ₂CHCOOH,CHCOOH); 2.9-3.0 (2H, d, PhCH₂CH₂); 6.9 (1H,s,Ar); 7.4 (1H,s,Ar).

[0223] 1) Preparation of (R,S)-2-amino-6-methyl-7-acetyltetralinehydro-chloride (ST 1274) 10

[0224] 6.5 g (0.028 moles) of(R,S)-6-methyl-7-acetyl-1,2,3,4-tetrahydro-2-naphthoic acid 9 weresuspended in 40 mL of anhydrous acetone; 4.3 mL (0.0307 moles) oftriethylamine were slowly added dropwise to the suspension. The solutiontemperature was brought to −5° C. and 2.95 mL (0.0307 moles) ofethyl-chlorophormiate dissolved in 4 mL of acetone were slowly addeddropwise.

[0225] 3.65 g (0.056 moles) of sodium azide dissolved in 80 mL of waterwere added dropwise to the solution maintaining the temperature at 0°C.; the mixture thus obtained was kept under stirring at 0° C. for 1 h,obtaining a precipitate. After the addition of a further 80 mL of coldwater the solution was extracted with 100 is mL of toluene and theorganic solution dehydrated with anhydrous sodium sulphate.

[0226] The solution was added to 30 mL of toluene heated to 100° C., andmaintained at 100° C. for a further 1.5 hours.

[0227] The solvent was removed for evaporation under vacuum obtaining4.9 g of dense lightly stained oil which was suspended in 50 mL of 8NHCl and heated to 100° C. under stirring for 1.5 h.

[0228] The solvent was removed for evaporation under vacuum; 100 mL ofwater were then added and the suspension was brought to pH 10 understirring with 4 N sodium carbonate cooling in an ice bath.

[0229] The aqueous solution was divided into smaller amounts andextracted with 120 mL of ethyl ether. The organic phase was dehydratedwith anhydrous sodium sulphate and gaseous hydrochloric acid was bubbledinto the ether solution thus obtained.

[0230] The precipitate thereby obtained was filtered off under vacuumand dried in air to give 2.3 g of slightly stained solid that wascrystallised with a mixture of ethyl acetate/methanol.

[0231] The solid was brought to dryness in the oven to give 2 g ofcolourless crystalline product (yield 30%).

[0232] M.P.: 195-197° C. with decomposition.

[0233]¹H-NMR, (CD₃OD), Varian 300 MHz, δ (p.p.m.): 1.75-1.85(1H,m,CHHCHN⁺); 2.15-2.3 (1H,m,CHHCHN+); 2.42 (3H,s,CH ₃CO); 2.53(3H,s,CH ₃Ph); 2.8-3.0(4H,m,PhCH₂CHN+),PhCH₂CH₂); 3.5-3.65 (1H,m,CHN+);7.05 (1H,s,Ar); 7.6 (1H,s,Ar).

[0234] The methodological approach most widely employed for the purposesof assessing the possible protective effect of a substance in septicshock, in pre-clinical investigations, is the use of experimental modelsof intoxication with a toxic substance (exo- or endotoxin) injecteddirectly into the laboratory animal or released in massive amounts bythe infecting cells with which the animal is inoculated.

[0235] The description of the following pharmacological tests shows theresults obtained with some of the compounds according to the invention,in comparison with the reference compound(R,S)-2-amino-6-fluoro-7-methoxytetraline hydrochloride (ST 626).

[0236] As mentioned above, the compound ST626 is an already knowncompound, which is structurally similar to the compounds of theinvention and has a similar pharmacological activity.

[0237] These results demonstrate the preventive and therapeuticalefficacy of the compounds of the invention, and also provide indicationsas to the possible mechanisms of action responsible for the favourablepharmacological profile of the compounds, namely a drastic lowering ofinflammatory cytokine levels (TNF, IL-1β, IL-6 and IFN-γ) in the blood.

[0238] Evaluation of the Effect of ST 1238, ST 1274 and ST 1275 inMurine Models of Septic Shock

[0239] Male BALB/C mice (C. River) aged approx. 6 weeks were utilised(10 animals per experimental group).

[0240] The animals, housed in cages at 22±2° C. and 50±15% relativehumidity with 12 h of light (7 am-7 pm) and 12 h of darkness (7 pm-7 am)had unrestricted access to food and drinking water.

[0241] The substances utilised were: LPS (Escherichia coli serotypeO26:B6), batch 73570 (Difco), LPS (Salmonella typhosa) batch 81H4018(Sigma), SEB (Staphylococcus aureus), batch 144H4024 (Sigma), andD-galactosamine batch 031EE002485 (Merck).

[0242] The compounds tested were ST1238, ST 1274 and ST 1275.

[0243] The compound solution pH was corrected, where necessary, withNaOH 0.1 N (maintaining the solution cold and under stirring) to obtainvalues no lower than pH 5.5.

[0244] Lethality Induced by S. typhosa LPS

[0245] Animals were treated intraperitoneally (i.p.) with S. typhosaLPS. Prior to use, the endotoxin was first dissolved in sterile salineand then injected in a volume of 200 μL, at the dose of 27.0 mg/kg,corresponding to about the LD₈₀.

[0246] The compounds tested were administered intravenously (i.v.) in avolume of 200 μL of sterile saline at the dose approximatelycorresponding to 1/10 LD₅₀, 30 min before and again 5 min after theendotoxic challenge (LPS).

[0247] Lethality Induced by E. coli LPS in Mice Sensitised withD-Galactosamine

[0248] Animals were sensitised with D-galactosamine (1000 mg/kg, i.p.)and, at the same time, treated with E. coli LPS (0.30 mg/kg, i.p.) in atotal volume of 200 μL.

[0249] The dose of LPS utilised corresponded approximately to 1/10 LD₅₀in the animals sensitised with D-galactosamine.

[0250] The compounds tested were administered intravenously (i.v.) in avolume of 200 μL of sterile saline, at the dose approximatelycorresponding to 1/10 LD₅₀, 30 min before and 5 min after, or 5 and 30min after the LPS challenge.

[0251] Lethality Induced by SEB (Staphylococcus aureus) in MiceSensitised with D-Galactosamine

[0252] Animals were sensitised with D-galactosamine (1000-1500 is mg/kg,i.p.) and, at the same time, treated with the enterotoxin SEB (3 mg/kg,i.p.) in a total volume of 200 μL. The dose of SEB utilisedcorresponding to approximately the LD₈₀, was evaluated in a preliminaryexperiment.

[0253] The compounds tested were administered intravenously (i.v.) in avolume of 200 μL of sterile saline, at the dose approximatelycorresponding to 1/10 LD₅₀, 30 min before and 5 min after, or 5 min and30 min after the SEB challenge.

[0254] Survival was assessed daily for 10 days in all the experiments,taking note of the day when each animal died.

[0255] The statistical significance of the protective effect wasevaluated using a one-tailed Fisher's exact test.

[0256] Results

[0257] Lethality Induced by S. typhosa LPS

[0258] In this experimental model of endotoxic shock with S. typhosaLPS, the compounds ST 1274 and ST 1275 significantly reduce thelethality when administered pre- and post-challenge (p<0.01 and p<0.05,respectively) (Table 1). TAB 1 Effect of ST 1274 and ST 1275 i.v.administration on the lethality induced in mice by injection of S.typhosa LPS. Pre-/post-challenge treatment schedule (−30 and +5 min).Treatment Survival increase^(a) (dose) Dead/Total (%) P^(b) LPS control14/20 — — ST 626 (6 mg/kg, i.v.)  6/20 +40 <0.05 LPS control 18/20 — —ST 1274 (5.5 mg/kg, i.v.) 10/20 +40 <0.01 LPS control 10/10 — — ST 1275(4 mg/kg, i.v.)  6/10 +40 <0.05

[0259] Lethality Induced by E. coli LPS in Mice Sensitised withD-Galactosamine

[0260] Compound ST1238 significantly reduces the lethality with bothtemporal treatment protocols adopted (p<0.001 and p<0.01) (Tables 2 and3), whereas compounds ST 1274 and ST 1275 give rise to non-significantpercentage increases in survival (20%) only with the pre- andpost-challenge administration protocol (Table 2). TAB 2 Effect of ST1238, ST1274 and ST 1275 i.v. administration on the lethality induced byinjection of E. coli LPS in mice sensitised with D-galactosamine.Pre-/post-challenge treatment schedule (−30 and +5 min). TreatmentSurvival increase^(a) (dose) Dead/Total (%) P^(b) LPS + D-GalN control25/29 — — ST 626 (6 mg/kg, i.v.) 21/28 +11 ns LPS + D-GalN control 17/20— — ST 1238 (18 mg/kg, i.v.)  5/20 +60 <0.001 LPS + D-GalN control  7/10— — ST 1274 (5.5 mg/kg, i.v.)  5/10 +20 ns LPS + D-GalN control  7/10 —— ST 1275 (4 mg/kg, i.v.)  5/10 +20 ns

[0261] TAB 3 Effect of ST 1238 i.v. administration on the lethalityinduced by injection of E. coli LPS in mice sensitised withD-galactosamine. Post-challenge only treatment schedule (+5 and +30min). Treatment Survival increase^(a) (dose) Dead/Total (%) P^(b) LPS +D-GalN control 16/20 — — ST 1238 (18 mg/kg, i.v.)  7/19 +44 <0.01

[0262] Lethality Induced by SEB (Staphylococcus aureus) in MiceSensitised with D-Galactosamine

[0263] With this experimental model all the compounds reduce thelethality in comparison with controls (70%-90%) when administered 30 minbefore and 5 min after the challenge (Table 4). ST 1238 still maintainsan extremely significant protective effect in the post-challenge onlytreatment schedule (p<0.001) (Table 5). TAB 4 Effect of ST 1238, ST1274and ST 1275 i.v. administration on the lethality induced by injection ofLPS from SEB enterotoxin in mice sensitised with D-galactosamine. Pre-and post-challenge treatment schedule (−30 and +5 min). TreatmentSurvival increase^(a) dose Dead/Total (%) P^(b) SEB + D-GalN control15/20 — — ST 1238 (18 mg/kg, i.v.)  1/20 +70 <0.001 SEB + D-GalN control 9/10 — — ST 1274 (5.5 mg/kg, i.v.)  0/10 +90 <0.001 SEB + D-GalNcontrol  9/10 — — ST 1275 (4 mg/kg, i.v.)  1/10 +80 <0.01 

[0264] TAB 5 Effect of ST 1238 i.v. administration on the lethalityinduced by injection of LPS from SEB enterotoxin in mice sensitised withD-galactosamine. Post-challenge only treament schedule (+5 and +30 min).Treatment Survival increase^(a) (dose) Dead/Total (%) P^(b) SEB + D-GalNcontrol 18/20 — — ST 1238 (18 mg/kg, i.v.)  4/20 +70 <0.001

[0265] Evaluation of the Effect of ST 1238 on Serum TNF (Tumor NecrosisFactor) Levels Induced by LPS in Rat Blood Culture

[0266] Cultures of whole blood cells stimulated by LPS were utilised asan experimental model. This model, albeit with certain limitations,mimics the physiopathological aspects of endotoxiaemia, a syndrome inwhich gram-negative bacteria release lipopoly-saccharide into theblood-stream which thus comes into contact with the immune system cells.

[0267] In fact, this model has recently been adopted for the evaluationof potential inhibitors of the release of TNF and IL-1 (GC Rice et al.,Shock, 4:254-266, 1994. A J H Gearing et al., Nature, 370:555-557, 1994.K Tschaikowsky, Biochim. Biophys. Acta, 1222:113-121, 1994. A Haziot etal, J. Immunol., 152:5868-5876, 1994).

[0268] Male Wistar rats (C. River) weighing about 175-200 g wereutilised.

[0269] The animals, housed in cages at 22±2° C. and 50±15% relativehumidity with 12 h of light (7 am-7 pm), had unrestricted access to foodand drinking water.

[0270] The compound tested was ST 1238.

[0271] The endotoxin utilised was: LPS from Salmonella typhosa batch81H4018 (Sigma).

[0272] Treatment of Blood Samples

[0273] Heparinised blood samples, 0.450 mL/vials, were taken from Wistarrats sacrificed by decapitation.

[0274] Volumes of 0.025 mL (solution 20×) of the test compounds (finalconcentration of 0.050 mM) dissolved in sterile saline were added to thevials containing the blood samples.

[0275] 0.025 mL (sol 20×) of Salmonella typhosa LPS (final concentrationin LPS equal to 1 μg/mL) were added to the samples incubated for 1 h at37° C. in a humidified atmosphere with 5% CO₂.

[0276] The samples were incubated in the same conditions for 4 h andthen centrifuged for 5 min at 10,000 rpm and the supernatant was storedat −80° C. pending TNF assay.

[0277] TNF biological activity was determined in RPMI medium containing1% FCS.

[0278] TNF Biological Assay

[0279] For the TNF assay serial dilutions of the samples (50 μL)containing TNF were made directly into Primaria 96-well microtiterplates; actinomycin D-mannitol (50 μL) at a final concentration of 4μg/mL, prepared in RPMI medium added with 1% FCS, was added to thewells. This inhibitor enhances the cells sensitivity to TNF.

[0280] 100 μL of a suspension (standardised at 4×10⁵ cells/mL) of L929(murine fibrosarcoma sensitive to the toxic action of TNF) weredispensed into each well. Appropriate controls, i.e. the actinomycin-Dcontrol (cells+actinomycin-D but without TNF) and the cell control(cells+culture medium alone) were also prepared.

[0281] After further incubation for 18 h at 37° C. with 5% CO₂, thecells were stained with a freshly prepared solution of 1 mg/mL XTT(sodium3′-[1-[(phenylamino)-carbonyl]-3,4-tetrazolium]-bis(4-meth-oxy-6-nitro)benzene-sulphonicacid hydrate) and 125 μM PMS (phenazine methosulphate) according to themethod described here below.

[0282] The XTT is dissolved (1 mg/mL) in RPMI medium at 60° C.

[0283] The PMS mother solution 100 mM (stable for about 20 days at +4°C. in the dark) is prepared by dissolving the PMS in PBS followed bybrief sonication so as to fully dissolve the PMS. The 100 mM PMSsolution is then diluted 1:800 in XTT, obtaining a final concentrationof 125 μM in PMS and 1 mg/mL in XTT. The staining mixture must befiltered prior to use.

[0284] Cells were stained by adding 50 μL/well of the XTT-PMS stainingsolution, obtaining a final volume of 250 μL/well with finalconcentrations of 0.2 mg/mL in XTT and 25 μM in PMS, respectively. A“blank was also prepared in wells containing 200 μL of culture medium+50μL of XT-PMS solution.

[0285] The microtiter plates are incubated for 2-2.5 h at 37° C. with 5%CO₂ (total incubation time=about 20 h).

[0286] The absorbance values of each sample were measured with amicrotiter plate reader at a reading wavelength of 450 nm and areference wavelength of 620 nm (the microtiter plate reader wasprogrammed to deduct the value obtained for the “blank” from the samplevalue).

[0287] The TNF titre was calculated using the following method. Bydefinition, 1 unit of biological activity is given by the semimaximalvalue (=50%) of the actinomycin-D absorbance.

[0288] Sample dilutions give rise to an absorbance value curve whoselinear portion is described by the equation y=ax+b.

[0289] After inserting the a and b values (obtained from the linearregression analysis done by the computer) and after substituting thesemimaximal absorbance value (corresponding to 1 biological unit) of theactinomycin-D control for y, the equation is solved for x, whichrepresents the reciprocal of the sample dilutions.

[0290] The value obtained gives the TNF titre in U/mL.

[0291] Data were analysed statistically using the two-tailed Student's ttest.

[0292] RESULTS

[0293] The results obtained (Table 6) show that compound ST 1238 reduces(39%) TNF production by rat blood cultures stimulated with LPS. TAB 6Effect of ST 1238 on TNF production induced in rat blood cultures (n =5) stimulated with S. typhosa LPS (1 μg/mL). The compounds were testedat a concentration of 50 μM. The experimental conditions are thosedescribed in Materials and Methods. TNF (mean % Treatment values) Stand.Dev. P* LPS control 100 0 — LPS + ST 1238 61 25 <0.01

[0294] Evaluation of the Effect of ST 1238 on Serum TNF Levels in TwoMurine Shock Models.

[0295] Male BALB/c mice (C. River), aged approx. 6 weeks were utilised(10 animals per experimental group).

[0296] The animals, housed in cages at 22±2° C. and 50±15% relativehumidity with 12 h of light (7 am-7 pm) and 12 h of darkness (7 pm-7am), had unrestricted access to food and drinking water.

[0297] The compound tested was ST 1238.

[0298] The substances utilised were: LPS (from E. coli serotype O26:B6,batch 73570 JB (Difco), SEB (Staphylococcus aureus) batch 144H4024(Sigma), D-galactosamine batch 031EE002485 (Merck).

[0299] Lethality Induced by E. coli LPS in Mice Sensitised withD-Galactosamine

[0300] The experimental conditions were exactly the same as thosepreviously described.

[0301] Lethality Induced by SEB (Staphylococcus aureus) in MiceSensitised with D-Galactosamine

[0302] The experimental conditions were exactly the same as thosepreviously described.

[0303] Blood Samples

[0304] In both experimental models, blood samples were taken 90 minafter the challenge (peak serum TNF level).

[0305] Ether-anaesthetised mice were bled by retro-orbital sinuspuncture.

[0306] Blood samples were incubated at room temperature for 2 h and theserum thus obtained was centrifuged for 20 min at 3000 rpm and stored at−80° C. pending TNF assay.

[0307] TNF Biological Assay

[0308] TNF biological activity was determined in RPMI medium containing1% FCS.

[0309] 50 μL/well of serial dilutions of samples containing TNF wereadded directly to the Primaria microtiter plates.

[0310] The experimental conditions utilised were the same as thosepreviously described. Data were analysed statistically using theone-tailed Student's t test.

[0311] Results

[0312] Lethality Induced by E. coli LPS in Mice Sensitised withD-Galactosamine

[0313] The results obtained in this experimental model are reported inTable 7. Compound ST 1238 significantly reduces TNF levels induced by E.coli LPS with both treatment schedules (pre-/post- and post-challengeonly; p<0.008 and p<0.0O01, respectively). TAB 7 Effect of ST 1238, 18mg/kg, i.v. administration on TNF production by injection of E. coli LPSin mice sensitised with D-galactosamine. Pre- and post-challengetreatment schedule (−30 and +5 min) and post-challenge only treatmentschedule (+5 and +30 min). −30/+5 min schedule +5/+30 min shedule TNF(U/mL) TNF (U/mL) Treatment Mean S.D. P Mean S.D. P LPS control* 154.241.0 — ST 626 (6 mg/kg, i.v.) 35.0 10.0 <0.01  LPS + D-GalN control 13.64.7 — 18.1 1.8 — ST 1238 0.4 0.2   0.008 2.2 0.6 0.0001

[0314] Lethality Induced by Enterotoxin SEB in Mice Sensitised withD-Galactosamine

[0315] The results obtained (Table 8) with this experimental model ofTNF production induced by LPS from SEB enterotoxin in animals sensitisedwith D-galactosamine show that compound ST 1238 significantly reducesTNF production both with the pre-/post-challenge schedule (p<0.0001) andwith the post-challenge only schedule (p<0.0002). TAB 8 Effect of ST1238, 18 mg/kg, i.v. administration on TNF production induced by LPSfrom SEB enterotoxin in mice sensitised with D-galactosamine. Pre- andpost-challenge (−30 and +5 min) and post- challenge only treatmentschedule (+5 and +30 min). −30/+5 min schedule +5/+30 min schedule TNF(U/mL) TNF (U/mL) Treatment Mean S.D. P mean S.D. P SEB + D-GalN control240.9 49.4 — 240.9 49.4 — ST 1238 6.2 3.0 0.0001 27.0 3.9 0.0002

[0316] Evaluation of the Effect of ST 1238 on Serum Interleukin-1 Beta(IL-1 β), Interleukin-6 (IL-6) and Interferon-Gamma (IFN-γ) Induced byEnterotoxin SEB, in Mice

[0317] Male BALB/c mice (C. River), aged approx. 6 weeks were utilised(10 animals per experimental group).

[0318] The animals, housed in cages at 22±2° C. and 50±15% relativehumidity with 12 h of light (7 am-7 pm) and 12 h of darkness (7 pm-7am), had unrestricted access to food and drinking water.

[0319] The compound tested was ST1238.

[0320] The substances utilised were LPS from SEB (Staphylococcusaureus), batch 144H4024 (Sigma) and D-galactosamine batch 031EE002485(Merck).

[0321] Lethality was induced by S. aureus SEB in mice sensitised withD-galactosamine.

[0322] The experimental conditions were exactly the sane as thosepreviously described.

[0323] Blood Samples

[0324] Blood samples were taken 2 h post-challenge for IL-6; 4 hpost-challenge for IL-1β and 6 h post-challenge for IFN-g.

[0325] Ether-anaesthetised mice were bled by retro-orbital sinuspuncture. Blood samples were incubated at room temperature for 2 h andthe serum thus obtained was centrifuged for 20 min at 3000 rpm andstored at −80° C. until assayed.

[0326] Biological Tests

[0327] Biological tests were performed according to the proceduresindicated in the respective assay kits utilised:

[0328] Mouse IL-1β Immunoassay (MLB00. R&D Systems)

[0329] Mouse IL-6 EIA Kit (8-6706,PerSeptive Diagnostics)

[0330] Mouse IFN-γ EIA Kit (8-6716,PerSeptive Diagnostics).

[0331] Data were analysed statistically using the one-tailed Student's ttest.

[0332] Results

[0333] Compound ST 1238 significantly reduces the production of theinflammatory cytokines assayed (p<0.001 for IL-1β; 0.0001 for IL-6; 0.01for IFN-γ); the results obtained are reported in Table 9. TAB 9 Effectof ST 1238, 19 mg/kg, i.v. administration on serum levels of IL-1β, IL-6and IFN-γ in model of intoxication with LPS from S. aureus SEB in micesensitised with D- galactosamine Pre- and post-challenge treatmentschedule (−30 and +5 min). IL-1β IL-6 IFN-γ (pg/mL) (pg/mL) (pg/mL)Treatment Mean s.e. P Mean s.e. P Mean s.e. P SEB + 18 4 — 3493 558 — 403 — D-galactosamine control ST 1238 0.9 0.5 0.001 599 163 0.0001 25 40.01

1. 2-Aminotetralines having formula (I)

or their pharmacologically acceptable salts having formula (II)

wherein: R and R₁, are independently, halogen; hydroxy; C1-C4 alkoxy,optionally substituted in position ω with groups OH, NH₂, NR₃R₄, whereinR₃ and R₄ are independently H, C1-C4 alkyl, unsubstituted or substitutedin position ω with groups OH, NH₂; C1-C4 alkanoyl; C1-C4 alkyl;carbamoyl; carbamoyloxy; amino; amino substituted NR₃R₄, where R₃ and R₄have the aforesaid meanings; R₂ is hydrogen; halogen; hydroxy; methoxy;with the proviso that the case is excluded in which the 2-aminotetralineis a raceme in which (a) R═R₁═CH₃O; OH; R₂═H; or (b) R═F R₁═CH₃O; OH;R₂═H; X⁻ is the monovalent anion of a pharmacologically acceptable acid.2. Compound according to claim 1, wherein the monovalent anion of apharmacologically acceptable acid is selected from chloride bromide,orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acidfumarate, lactate, maleate and acid maleate, acid oxalate, acidsulphate, glucose phosphate, tartrate and acid tartrate.
 3. A compoundaccording to claim 1 which is selected from;S(−)-2-amino-6-fluoro-7-hydroxytetraline hydrochloride (ST 1237);R(+)-2-amino-6-fluoro-7-hydroxytetraline hydrochloride (ST 1238);(R,S)-2-amino-5,6-difluoro-7-methoxytetraline hydrochloride (ST 1269);(R,S)-2-amino-6-fluoro-7-methyltetraline hydrochloride (ST 1275);(R,S)-2-amino-7-fluoro-6-hydroxytetraline hydrochloride (ST 1267);(R,S)-7-acetyl-2-amino-6-methyltetraline hydrochloride (ST 1274);(R,S)-2-amino-7-fluoro-6-methoxytetraline hydrochloride (ST 1262).
 4. Anorally or parenterally administrable pharmaceutical compositioncontaining a compound of formula I or II and a pharmaceuticallyacceptable carrier and/or diluent.
 5. An orally or parenterallyadministrable pharmaceutical composition for the prevention andtherapeutical treatment of inflammatory and/or autoimmune pathologiesinduced by inflammatory cytokines, and which comprises as activeingredient a compound according to claim 1, 2 or 3 and apharmacologically acceptable excipient.
 6. Composition according toclaim 5, for the prophylactic and the therapeutical treatment of septicshock.
 7. Composition according to claim 5, for preparing a medicamentfor the therapeutic treatment of rheumatoid arthritis, pancreatitis,inflammatory bowel disease, systemic lupus erythematosus,glomerulonephritis and encephalomyelitis.